Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss.

Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.

Population-Based Comparison of Different Risk Stratification Systems Among Prostate Cancer Patients.

BACKGROUND: It is not known which risk stratification system has the best discrimination ability for predicting prostate cancer death. METHODS: We identified patients with non-metastatic primary prostate adenocarcinoma diagnosis between 2004 and 2015 using the Surveillance, Epidemiology, and End Results database. Patients were categorized in different risk groups using the three frequently used risk stratification systems of the National Comprehensive Cancer Network guideline (NCCN-g), American Urological Association guideline (AUA-g), and European Association of Urology guideline (EAU-g), respectively. Associations between risk classification and prostate cancer-specific mortality (PCSM) were determined using Kaplan-Meier analyses and multivariable regression with Cox proportional hazards model. Area under the receiver operating characteristics curve (AUC) analyses were used to test the discrimination ability of the three risk grouping systems. RESULTS: We analyzed 310,062 patients with a median follow-up of 61 months. A total of 36,368 deaths occurred, including 6,033 prostate cancer deaths. For all the three risk stratification systems, the risk groups were significantly associated with PCSM. The AUC of the model relying on NCCN-g, AUA-g, and EAU-g risk stratification systems for PCSM at specifically 8 years were 0.818, 0.793, and 0.689 in the entire population; 0.819, 0.795, and 0.691 in Whites; 0.802, 0.777, and 0.681 in Blacks; 0.862, 0.818, and 0.714 in Asians; 0.845, 0.806, and 0.728 in Chinese patients. Regardless of the age, marital status, socioeconomic status, and treatment modality, AUC of the model relying on NCCN-g and AUA-g for PCSM was greater than that relying on EAU-g; AUC of the model relying on NCCN-g system was greater than that of the AUA-g system. CONCLUSIONS: The NCCN-g and AUA-g risk stratification systems perform better in discriminating PCSM compared to the EAU-g system. The discrimination ability of the NCCN-g system was better than that of the AUA-g system. It is recommended to use NCCN-g to evaluate risk groups for prostate cancer patients and then provide more appropriate corresponding treatment recommendations.

Cordyceps sinensis Promotes the Growth of Prostate Cancer Cells.

BACKGROUND: This study aims to test whether Cordyceps sinensis (CS), the most expensive Asian nutrient supplement might stimulate growth of prostate cancer cells. METHODS: Impact of CS on growth of prostate cancer was determined in vivo and in vitro. RESULTS: Firstly, the serum testosterone level was significantly elevated in mice fed CS. Prostate glands were significantly enlarged (weight index 0.53 ± 0.04 mg/g vs. 0.31 ± 0.04 mg/g, P = 0.006). Furthermore, cell viability was increased twofold in the androgen-responsive prostate cancer cell line (VCaP) after CS treatment. This promoting effect disappeared after bicalutamide was added. In addition, serum prostate-specific antigen (PSA) in mice bearing VCaP xenografts was significantly elevated (0.66 ± 0.04 ng/ml vs. 0.26 ± 0.06 ng/ml, P < 0.001) after treatment with CS. Finally, VCaP tumors in mice treated with CS grew much faster (479.2 ± 78.74 mm3 vs. 283 ± 58.97 mm3, P = 0.074). However, the above promoting effects of CS were not observed in parallel studies using the PC-3 cell line which lacks AR expression. CONCLUSIONS: These results suggest that CS promotes growth of prostate cancer cells by increasing production of testosterone and stimulating the AR-dependent pathway. Additional studies are required to see whether CS is safely consumed by patients with prostate cancer.

Flavonoids from Mirabilis himalaica.

Six previously undescribed flavonoids, 2S-5-methoxy-6-methyl-7,2'-dihydroxyflavanone, 5,7,2'-trihydroxy-6-methylflavone, 5,7,6'-trihydroxy-6-methylcoumaronochromone, 2,4',6'-trihydroxy-2'-methoxy-3'-methylchalcone, 6R,11-dimethoxy-9-hydroxyrotenoid, and 6R,11-dimethoxy-9-hydroxy-10-methylrotenoid, along with eight known flavonoids, including 2S-5-methoxy-6-methyl-7,4'-dihydroxyflavanone, not previously reported as a natural product, and seven rotenoids, boeravinone A, B, D, P, F, coccineone B, and mirabijalone E, were isolated from the ethyl acetate soluble fraction of Mirabilis himalaica roots. Their structures were established by the extensive spectroscopic analysis, including HRESIMS, UV, NMR and ECD. All compounds were evaluated for their cytotoxic activities against three human cancer cell lines: A375 (melanoma), A549 (lung), and PLC (hepatoma).

Cloning of a putative extracellular Cu/Zn superoxide dismutase and functional differences of superoxide dismutases in invasive and indigenous whiteflies.

Superoxide dismutases (SODs) are a group of important antioxidant defense enzymes. In this study, a putative extracellular Cu/Zn superoxide dismutase (ecCuZnSOD) complementary DNA was cloned and characterized from the whitefly, Bemisia tabaci. Quantitative polymerase chain reaction analysis showed that the expression level of BtecCuZnSOD was more than 10-fold higher in the invasive Middle East Asia Minor 1 (MEAM1) than in the native Asia II 3 species of the B. tabaci species complex. After exposure to low temperature (4 °C), the expression of Bt-ecCuZnSOD gene was significantly up-regulated in MEAM1 but not in Asia II 3. Furthermore, the expression level of B. tabaci intracellular CuZnSOD (Bt-icCuZnSOD), Bt-ecCuZnSOD and mitochondrial MnSOD (Bt-mMnSOD) was compared after transferring MEAM1 and Asia II 3 whiteflies from favorable (cotton) to unfavorable host plants (tobacco). On cotton, both CuZnSOD genes were expressed at a higher level in MEAM1 compared with Asia II 3. Interestingly, after transferring onto tobacco, the expression of Bt-ecCuZnSOD was significantly induced in Asia II 3 but not in MEAM1. On the other hand, while Bt-mMnSOD was expressed equally in both species on cotton, Bt-mMnSOD messenger RNA was up-regulated in MEAM1 on tobacco. Consistently, enzymatic activity assays of CuZnSOD and MnSOD demonstrated that CuZnSOD might play an important protective role against oxidative stress in Asia II 3, whereas MnSOD activation was critical for MEAM1 whiteflies during host adaptation. Taken together, our results suggest that the successful invasion of MEAM1 is correlated with its constitutive high activity of CuZnSOD and inducible expression of MnSOD under stress conditions.

[Chemical constituents from the twigs and leaves of Harrisonia perforate].

This study was performed to investigate the chemical constituents in the twigs and leaves of Harrisonia perforate. Six compounds were isolated from the 95% EtOH extract of the twigs and leaves of Harrisonia perforate by silica gel, ODS, Sephadex LH-20 column chromatographies and preparative HPLC. On the basis of chemical properties and spectra data, these compounds were identified as harriperfin E (1), kihadanin A (2), kihadanin B (3), 6α-acetoxyobacunol acetate (4), gardaubryone C (5), and ß-sitosterol methyl ether (6), respectively. Compound 1 is a new chromone, and compounds 2-6 are isolated from this plant for the first time.

[Interference of vitamin E on the brain tissue damage by electromagnetic radiation of cell phone in pregnant and fetal rats].

OBJECTIVE: To investigate the interlerence ot vitamin E on brain tissue damage by electromagnetic radiation of cell phone in pregnant and fetal rats. METHODS: 40 pregnant rats were randomly divided into five groups (positive control, negative control, low, middle and high dosage of vitamin E groups). The low, middle and high dosage of vitamin E groups were supplemented with 5, 15 and 30 mg/ml vitamin E respectively since the first day of pregnancy. And the negative control group and the positive control group were given peanut oil without vitamin E. All groups except for the negative control group were exposed to 900MHz intensity of cell phone radiation for one hour each time, three times per day for 21 days. After accouchement, the right hippocampus tissue of fetal rats in each group was taken and observed under electron microscope. The vitality of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the content of malondialdehyde (MDA) in pregnant and fetal rats' brain tissue were tested. RESULTS: Compared with the negative control group, the chondriosomes in neuron and neuroglia of brain tissues was swelling, mild edema was found around the capillary, chromatin was concentrated and collected, and bubbles were formed in vascular endothelial cells (VEC) in the positive fetal rat control group, whereas the above phenomenon was un-conspicuous in the middle and high dosage of vitamin E groups. We can see uniform chromatin, abundant mitochondrion, rough endoplasmic reticulum and free ribosomes in the high dosage group. The apoptosis has not fond in all groups'sections. In the antioxidase activity analysis, compared with the negative control group, the vitality of SOD and GSH-Px significantly decreased and the content of MDA significantly increased both in the pregnant and fetal rats positive control group (P < 0.05). In fetal rats, the vitality of SOD and GSH-Px significantly increased in the brain tissues of all three different vitamin E dosages groups when compared with the positive control group, and the content of MDA was found significantly decreased in both middle and high dosage of vitamin E groups(P < 0.05). The same results have also been found in high dosage pregnant rat group, but in middle dosage group only SOD activity was found increased with significance (P < 0.05). With the dosage increase of vitamin E, the vitality of SOD and GSH-Px was increasing and the content of MDA was decreasing. CONCLUSION: Under the experimental dosage, vitamin E has certain interference on damage of antioxidant capacity and energy metabolization induced by electromagnetic radiation of cell phone in pregnant rats and fetal rats.

Considerations of treatment standardization from the procession of NCCN guideline of esophageal cancer.

Esophageal carcinoma is one of the most common malignant tumors, especially in China which is the high incidence area. As a result of mild symptoms of early-stage esophageal cancer, the majority of patients cannot be diagnosed until they develop to advanced cancer, and the treatment outcome of surgery or chemoradiotherapy is still unsatisfactory at present. The guidelines of esophageal cancer issued by National Comprehensive Cancer Network (NCCN) are regarded as important reference tools by clinical oncologists, and provide uniform criteria for the diagnosis and treatment of esophageal carcinoma. However, the guidelines are not always suitable for Chinese patients because the data come from European and American population which have significant ethnical difference from Chinese. We retrospectively analyzed the changes of treatment strategy of esophageal cancer in NCCN guidelines and the advance of treatment for esophageal carcinoma in China, aiming to provide our oncologists with new research ideas. We also hope to set up clinical cancer cooperation organizations, and release our own cancer guidelines to serve Chinese patients and oncologists.

[Application of metabolomics in research of plant metabolites].

Metabolomics, a branch of systems biology, has gained extensive attention and profound achievements in the plant. Although plant metabolomics is to be explored, it has been one of the most effective methods to study the physiological and biochemical process and gene modification in pattern plants. We herein summarized the concept, development, and application of metabolomics and prospected the potentials in the metabolite profiling for plant. Metabolomics provides an omics' methodology to elucidate the whole biological process, identify and quantify the complex components in the plant. A number of metabolites present in the plant are active components of traditional Chinese medicine, and these bioactive components are influenced by the multi-factors such as environment, species, and processing methods etc. Therefore, it is of great importance to analyze a wide spectrum of compositions with diverse chemical characteristics and varied concentration, which is the foundation to quality control, allowing the elucidation of the pharmacological effectiveness, and further exploiting of traditional Chinese medicine.

Analysis of dencichine in Panax notoginseng by gas chromatography-mass spectrometry with ethyl chloroformate derivatization.

Dencichine (beta-N-oxalyl-l-alpha,beta-diaminopropionic acid) is a haemostatic agent present in well-known traditional Chinese medicinal herbs such as Panax notoginseng, as well as other Panax species. It is also a reported neurotoxic agent found in Lathyrus sativus (grass pea seed) and cycad seeds. A method was developed for quantitative determination of the non-protein amino acid, dencichine, in plant samples of P. notoginseng and the adventitious roots directly from the explants of P. notoginseng after derivatization with ethyl chloroformate (ECF) by gas chromatography-mass spectrometry (GC-MS). l-2-chlorophenylalanine was used as an internal standard. Calibration curves were linear (r(2)=0.9988, n=6) in the range of 10-800 microg/ml for dencichine. Limit of detection and quantification for dencichine were 0.5 microg/ml and 2 microg/ml, respectively. This rapid and specific method may be applied to the quantification of dencichine in complex medicinal plants and their products.

[Adventitious root induction and in vitro culture of Panax notoginseng].

OBJECTIVE: To investigate the induction and culture of adventitious root of Panax notoginseng. METHOD: Three ways, induction from the explants of three-year-old P. notoginseng. The explants of regenerated shoots and calluses, were used to induce adventitious roots. The effects of 2, 4-dichlorophenoxyacetic acid, indole-3-butyric acid and naphthylacetic acid on adventitious root induction were investigated respectively. The effects of four modes of separating adventitious roots from the parent tissues on culture in vitro were compared. RESULT: Adventitious roots were successfully induced by three methods, of which the young flower bud callus was the best material for the induction of adventitious root. Indole-3-butyric acid possessed the strongest potency for induction. The liquid culture system was established by continuous culture of adventitious roots together with their parent tissues before separated. CONCLUSION: The acquisition and culture in vitro in liquid culture system of adventitious roots of P. notoginseng lay a foundation for the next investigation.

[Local thermotherapy with rabdosia liquid as prophylactic measure for recurrence of superficial urinary bladder carcinoma: a non-randomized contemporary controlled study].

OBJECTIVE: To compare the actions of local thermotherapy with rabdosia liquid and repeated perfusion of mitomycin C for the postoperative prophylaxis of superficial urinary bladder carcinoma. METHODS: In the prospective non-randomized contemporary controlled study, 123 patients were divided into 2 groups. The patients in group A received local thermotherapy with rabdosia liquid starting from 1-2 months after operation, once tri-monthly for one year. Those in group B received intravesical perfusion of mitomycin C, starting from 2 weeks after operation, once weekly, six times in total, thereafter once monthly for one year. The recurrence rate, disease free interval, and adverse reaction after operation were observed. RESULTS: The follow-up lasted for 10-45 months with the average of 28.6 +/- 5.8 months. The recurrence rates in group A and B were 5.0% and 14.3%, respectively. Significant difference was shown when compared by Kaplan-Meier analysis of disease free interval and the recurrence rate between the two groups (P < 0.05). The occurrence rates of cystitis, hematuria, vesical contracture, urethral stricture were 28.3%, 5.0%, 1.7%, 1.7%, respectively in group A, 25.4%, 4.8%, 0%, 0%, respectively in group B, showing no significant difference between the two groups (P > 0.05). CONCLUSION: The effect of local thermotherapy with rabdosia liquid is reliable in preventing the recurrence of superficial urinary bladder transitional cell carcinoma.

Local thermotherapy with rabdosia liquid as prophylactic measure for recurrence of superficial urinary bladder carcinoma: a non-randomized contemporary controlled study / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To compare the actions of local thermotherapy with rabdosia liquid and repeated perfusion of mitomycin C for the postoperative prophylaxis of superficial urinary bladder carcinoma.</p><p><b>METHODS</b>In the prospective non-randomized contemporary controlled study, 123 patients were divided into 2 groups. The patients in group A received local thermotherapy with rabdosia liquid starting from 1-2 months after operation, once tri-monthly for one year. Those in group B received intravesical perfusion of mitomycin C, starting from 2 weeks after operation, once weekly, six times in total, thereafter once monthly for one year. The recurrence rate, disease free interval, and adverse reaction after operation were observed.</p><p><b>RESULTS</b>The follow-up lasted for 10-45 months with the average of 28.6 +/- 5.8 months. The recurrence rates in group A and B were 5.0% and 14.3%, respectively. Significant difference was shown when compared by Kaplan-Meier analysis of disease free interval and the recurrence rate between the two groups (P < 0.05). The occurrence rates of cystitis, hematuria, vesical contracture, urethral stricture were 28.3%, 5.0%, 1.7%, 1.7%, respectively in group A, 25.4%, 4.8%, 0%, 0%, respectively in group B, showing no significant difference between the two groups (P > 0.05).</p><p><b>CONCLUSION</b>The effect of local thermotherapy with rabdosia liquid is reliable in preventing the recurrence of superficial urinary bladder transitional cell carcinoma.</p>

Cepharanthine enhances in vitro and in vivo thermosensitivity of a mouse fibrosarcoma, FSa-II, based on increased apoptosis.

Cepharanthine (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. In our previous study, Ce significantly enhanced thermosensitivity and thereby reduced thermotolerance in vitro, and intra-peritoneal injection of Ce slightly enhanced thermosensitivity in vivo. In the present study, we investigated Ce's effect in vitro on the pattern of cell death after heating and the effect of intra-tumoral injection of Ce on in vivo thermosensitivity using a mouse fibrosarcoma, FSa-II, and C3H/He mice. Ce significantly enhanced the in vitro thermosensitivity of FSa-II cells with heating at 44 degrees C, with increased Ce concentration. Time-lapse microscopic observation of individual cells confirmed that Ce treatment hastened both apoptosis (specifically, apoptotic budding) and necrosis (as indicated by staining with propidium iodide). Staining with annexin V-enhanced green fluorescent protein indicated that Ce used concomitantly with heating significantly increased the proportion of cells in the early stage of apoptosis. Ce combined with heating also significantly increased the proportion of cells with high intracellular caspase-3 activity, as detected by a substrate of caspase-3, PhiPhiLux-G1D2. The intra-tumoral injection of Ce, followed by heating at 44 degrees C, significantly delayed in vivo tumor growth, and this delay increased in a Ce concentration-dependent manner. Ce injected 30 min before heating delayed tumor growth more than Ce injected immediately before heating. These findings suggest the potential of Ce as a thermosensitizer to increase apoptosis of tumor cells.